Exercise effects on perivascular adipose tissue: endocrine and paracrine determinants of vascular function

Obesity is a global epidemic, accompanied by increased risk of type 2 diabetes and cardiovascular disease. Adipose tissue hypertrophy is associated with adipose tissue inflammation, which alters the secretion of adipose tissue-derived bioactive products, known as adipokines. Adipokines determine vessel wall properties such as smooth muscle tone and vessel wall inflammation. Exercise is a mainstay of prevention of chronic, non-communicable diseases, type 2 diabetes and cardiovascular disease in particular. Aside from reducing adipose tissue mass, exercise has been shown to reduce inflammatory activity in this tissue. Mechanistically, contracting muscles release bioactive molecules known as myokines, which alter the metabolic phenotype of adipose tissue. In adipose tissue, myokines induce browning, enhance fatty acid oxidation and improve insulin sensitivity. In the past years, the perivascular adipose tissue (PVAT) which surrounds the vasculature, has been shown to control vascular tone and inflammation through local release of adipokines. In obesity, an increase in mass and inflammation of PVAT culminate in dysregulation of adipokine secretion, which contributes to vascular dysfunction. This review describes our current understanding of the mechanisms by which active muscles interact with adipose tissue and improve vascular function. Aside from the exercise-dependent regulation of canonical adipose tissue function, we will focus on the interactions between skeletal muscle and PVAT and the role of novel myokines, such as IL-15, FGF21 and irisin, in these interactions. Linked Articles: This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue – Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc

Improvement of glycaemic control in type 2 diabetes: Favourable changes in blood pressure, total cholesterol and triglycerides, but not in HDL cholesterol, fibrinogen, von Willebrand factor and (pro)insulin

Background: Diabetes mellitus causes a substantial increase in cardiovascular risk, which can only partly be reduced by antihyperglycaemic treatment. We were interested in whether improvement in glycaemic control is associated with improvement of other cardiovascular risk factors. Therefore, we studied among type 2 diabetic patients the association between on the one hand changes in glycaemic control and on the other hand within-subject changes of both classic cardiovascular risk factors and less conventional cardiovascular risk indicators that are typically associated with type 2 diabetes (proinsulin, insulin, fibrinogen, von Willebrand factor and the urinary albumin-creatinine ratio). Methods: The 214 type 2 diabetic patients were randomly assigned to either a strict fasting capillary glucose target level (<6.5 mmol/l) or a less strict target (<8.5 mmol/l). Duration of follow-up was two years. Since the interventions did not yield statistically significant differences between the treatment arms, we reanalysed the data focusing on within-subject changes of cardiovascular risk factors and indicators across tertiles of average HbAIC. Results: Individuals in whom HbAIC decreased had significant favourable concurrent changes in triglycerides, total cholesterol, blood pressure, and in the albumin-creatinine ratio in those who were normoalbuminuric at baseline. In contrast, these individuals had unfavourable, although not statistically significant, changes in HDL cholesterol, proinsulin, insulin, fibrinogen and von Willebrand factor. In the whole group, fibrinogen increased more than could be expected on the basis of the relationship between fibrinogen and age, namely from 3.5 ± 0.8 to 3.9 ± 0.9 g/l (p value <0.01). Conclusions: Our results suggest that improvement in glycaemia in type 2 diabetes is associated with significant favourable changes in triglycerides, total cholesterol, blood pressure and, in normoalbuminuric individuals, albumin-creatinine ratio. In contrast, it is not consistently associated with favourable changes in some cardiovascular risk indicators typically associated with diabetes, which may in part explain why antihyperglycaemic treatment does not clearly lower atherothrombotic disease risk

The minor histocompatibility antigen 1 (HMHA1)/ArhGAP45 is a RacGAP and a novel regulator of endothelial integrity

Endothelial cells line the vasculature and act as gatekeepers that control the passage of plasma, macromolecules and cells from the circulation to the interstitial space. Dysfunction of the endothelial barrier can lead to uncontrolled leak or edema. Vascular leakage is a hallmark of a range of diseases and despite its large impact no specialized therapies are available to prevent or reduce it. RhoGTPases are known key regulators of cellular behavior that are directly involved in the regulation of the endothelial barrier. We recently performed a comprehensive analysis of the effect of all RhoGTPases and their regulators on basal endothelial integrity. In addition to novel positive regulators of endothelial barrier function, we also identified novel negative regulators, of which the ArhGAP45 (also known as HMHA1) was the most significant. We now demonstrate that ArhGAP45 acts as a Rac-GAP (GTPase-Activating Protein) in endothelial cells, which explains its negative effect on endothelial barrier function. Silencing ArhGAP45 not only promotes basal endothelial barrier function, but also increases cellular surface area and induces sprout formation in a 3D-fibrin matrix. Our data further shows that loss of ArhGAP45 promotes migration and shear stress adaptation. In conclusion, we identify ArhGAP45 (HMHA1) as a novel regulator, which contributes to the fine-tuning of the regulation of basal endothelial integrity

A CDC42-centered signaling unit is a dominant positive regulator of endothelial integrity

Endothelial barrier function is carefully controlled to protect tissues from edema and damage inflicted by extravasated leukocytes. RhoGTPases, in conjunction with myriad regulatory proteins, exert both positive and negative effects on the endothelial barrier integrity. Precise knowledge about the relevant mechanisms is currently fragmented and we therefore performed a comprehensive analysis of endothelial barrier regulation by RhoGTPases and their regulators. Combining RNAi with electrical impedance measurements we quantified the relevance of 270 Rho-associated genes for endothelial barrier function. Statistical analysis identified 10 targets of which six promoted-and four reduced endothelial barrier function upon downregulation. We analyzed in more detail two of these which were not previously identified as regulators of endothelial integrity. We found that the Rac1-GEF (Guanine nucleotide Exchange Factor) TIAM2 is a positive regulator and the Cdc42(Rac1)-GAP (GTPase-Activating Protein) SYDE1 is a negative regulator of the endothelial barrier function. Finally, we found that the GAP SYDE1 is part of a Cdc42-centered signaling unit, also comprising the Cdc42-GEF FARP1 and the Cdc42 effector PAK7 which controls the integrity of the endothelial barrier. In conclusion, using a siRNA-based screen, we identified new regulators of barrier function and found that Cdc42 is a dominant positive regulator of endothelial integrity

Effect of prior statin therapy on capillary permeability in the lungs after cardiac or vascular surgery

Cholesterol-lowering statins can ameliorate severe forms of vascular hyperper-meability in experimental studies, and may thereby amellorate acute lung injury and sepsis. It is unknown whether this also applies to humans. This study aimed to define whether or not prior statin therapy reduces mild post-operative increases in pulmonary capillary protein permeability associated with acute lung injury after cardiac or major vascular surgery. A prospective observational study was performed in an intensive care unit of a university hospital on 64 patients, 37 after elective cardiac and 27 after major vascular surgery, of whom 68 and 44%, respectively, had received prior statin therapy. A mobile probe system was used to measure the pulmonary leak index (PLI), i.e. the transvascular transport rate of gallium-67-radiolabelled transferrin. For all of the patients together, the mean PLI did not differ between the statin and control groups (22.9 versus 24.4 × 10-3 min-1). The prevalence of an elevated PLI was 57% in the statin and 59% in the control group. Subgroup analysis did not reveal significant differences caused by statins in the PLI of these patients. Prior statin therapy neither has an adverse effect on mildly increased pulmonary capillary permeability in patients after cardiac or major vascular surgery nor does it ameliorate this increased capillary permeability

Potential role of platelets in endothelial damage observed during treatment with cisplatin, gemcitabine, and the angiogenesis inhibitor SU5416

Purpose: An increased incidence of thromboembolic events was observed during treatment with cisplatin-gemcitabine plus SU5416 (CG+SU5416), a tyrosine kinase inhibitor targeting the vascular endothelial growth factor (VEGF) receptor-1 and -2. Nine thromboembolic events occurred in eight of 19 patients. We performed an analysis of parameters of the coagulation cascade and vessel wall activation. Materials and Methods: Markers for thrombin generation and endothelial cell activation were measured in three patients treated with CG+SU5416, two of whom developed a thromboembolic event. The results were compared with measurements in six patients treated with CG alone, and in 17 patients treated with SU5416 alone. Results: During cycles 1 and 2 of treatment with CG+SU5416, a significant cycle-dependent activation of both the coagulation cascade and endothelial cells occurred, whereas platelet counts decreased. Change in platelet number had a significant negative predictive effect on soluble (s)-E-selectin levels. Significant activation of the coagulation cascade only was observed in the patients treated with CG alone, whereas in patients treated with SU5416 alone, significant endothelial cell activation was observed. Conclusion: We hypothesize that endothelial cells deprived of VEGF after exposure to SU5416 became activated and more susceptible to damage during treatment with CG+SU5416, which was aggravated by a transient decrease in platelets, which are, among other things, carriers of VEGF. These results suggests that VEGF, in addition to being a permeability, proliferation, and migration factor, also is a maintenance and protection factor for endothelial cells, and that platelets may have a role in maintaining vascular integrity

Natural killer cells and CD4+ T-cells modulate collateral artery development

OBJECTIVE - The immune system is thought to play a crucial role in regulating collateral circulation (arteriogenesis), a vital compensatory mechanism in patients with arterial obstructive disease. Here, we studied the role of lymphocytes in a murine model of hindlimb ischemia. METHODS AND RESULTS - Lymphocytes, detected with markers for NK1.1, CD3, and CD4, invaded the collateral vessel wall. Arteriogenesis was impaired in C57BL/6 mice depleted for Natural Killer (NK)-cells by anti-NK1.1 antibodies and in NK-cell-deficient transgenic mice. Arteriogenesis was, however, unaffected in Jα281-knockout mice that lack NK1.1 Natural Killer T (NKT)-cells, indicating that NK-cells, rather than NKT-cells, are involved in arteriogenesis. Furthermore, arteriogenesis was impaired in C57BL/6 mice depleted for CD4 T-lymphocytes by anti-CD4 antibodies, and in major histocompatibility complex (MHC)-class-II-deficient mice that more selectively lack mature peripheral CD4 T-lymphocytes. This impairment was even more profound in anti-NK1.1-treated MHC-class-II-deficient mice that lack both NK- and CD4 T-lymphocytes. Finally, collateral growth was severely reduced in BALB/c as compared with C57BL/6 mice, 2 strains with different bias in immune responsiveness. CONCLUSIONS - These data show that both NK-cells and CD4 T-cells modulate arteriogenesis. Promoting lymphocyte activation may represent a promising method to treat ischemic disease